Project Summary Proteome quantification has become an increasingly essential component of modern biology and translational medicine. Whether targeted or global, stable isotope incorporation with mass spectrometry (MS) analysis is a core technique for protein abundance measurement. There are numerous approaches to introduce stable isotopes into peptides, the most frequently used being stable isotope labeling with amino acids in cell culture (SILAC) and isobaric tagging (e.g., tandem mass tags, TMT, or iTRAQ). These methods incorporate heavy isotopes to increase mass by at least 1 Da. SILAC, the quantification gold standard, for example, typically utilizes a 4 Da spacing to limit the isotopic cluster overlap of the heavy and light peptides. This requirement limits the quantitative capacity of SILAC to triplex. The reason for this is twofold: (1) the mass of the amino acids can only be elevated to ~ +12 Da; and (2) mass spectral complexity is increased as multiple isotopic clusters are introduced. Isobaric tagging eliminates the latter problem by concealing the quantitative information in the MS1 scan, thereby permitting a much higher level of multiplexing. That said, isobaric tagging, being a chemical tag, is not amenable to in vivo labeling. Further, quantitative data can only be obtained for peptides that are selected for MS2.